tbuckley/cabot-search huggingface dataset:
Preliminary results from a phase II study comparing sunitinib alone or with stereotactic body radiotherapy (SBRT) for newly diagnosed oligometastatic renal cell carcinoma.
Authors: Yang Liu, Wensu Wei, Zhiling Zhang, Ruiqi Liu, Jianming Gao, Shengjie Guo, Hui Han, Pei Dong, Liru He, Fangjian Zhou
Journal: Journal of Clinical Oncology (2023)

4533 Background: Although SBRT has become an option for oligometastatic renal cell carcinoma (oligoRCC), current trials supporting SBRT haven’t been adequately persuasive given their single-arm, non-first-line design. Our study aimed to explore if SBRT improves oncologic outcomes compared with standard first-line systemic therapy in oligoRCC. Methods: This an open-label, double-arm phase II controlled trial enrolling treatment naïve oligoRCC patients (pts), defined as ≤ 5 metastatic lesions (ChiCTR1800017136). No liver or brain metastasis was allowed. Nephrectomy was mandatory before enrollment. Pts were allocated 1:1 to receive either sunitinib alone (control arm) or sunitinib plus SBRT (SBRT arm). Sunitinib was started as 50 mg daily for 4 weeks, followed by 2 weeks off treatment. SBRT was delivered to all metastatic sites within 2 months after sunitinib initiation, with 35-50Gy in 5 fractions. Primary endpoint was objective response rate (ORR); secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. Data from pts with ≥ 1 year of follow-up were reported this time. Results: Starting in 2018, the trial has currently completed its accrual, with 48 pts enrolled. Forty-two pts had ≥ 1 year of follow-up and were evaluable for the present analysis. Pt characteristics for SBRT and control arms: median age 51 vs 59 years (p=0.094); synchronous metastasis 31.8% vs 10.0% (p=0.179); clear cell carcinoma 77.3% vs 80.0% (p=1.000); IMDC low or intermediate risk 86.4% vs 80.0% (p=1.000); solitary metastasis 45.5% vs 25.0% (p=0.167). Thirty-four sites received SBRT, most frequently to bone (61.8%) and soft tissue (17.6%) metastasis. The 1-year local control rate after SBRT was 93.8%. ORR (81.8% vs. 25.0%, p=0.000) and DCR (90.9% vs. 60.0%, p=0.047) were significantly higher in SBRT arm than those in control arm. The 1y-PFS was 72.7% for SBRT arm and 35.0% for control arm (HR 0.33, 95% CI 0.16-0.69, p= 0.003). And the 1y-OS was 95.5% for SBRT arm and 80.0% for control arm (HR 1.06, 95% CI 0.31-3.67, p=0.923). Grade 3-4 treatment-related AEs occurred in 66.7% and 62.5% pts in SBRT arm and control arm (p=0.763), respectively. SBRT-related Grade 3-4 toxicity included radiation enteritis (n=1, grade 3) and radiation pneumonitis (n=1, grade 3). Conclusions: Our results showed promising efficacy and acceptable toxicity of SBRT plus sunitinib when compared with sunitinib alone for oligoRCC. Complete results are awaited in 2023 after follow-up completion of the entire cohort. Clinical trial information: ChiCTR1800017136.
Current treatment outcomes of congenital heart disease and future perspectives
Authors: Kai Ma, Qiyu He, Zheng Dou, Xiaotong Hou, Xi Li, Ju Zhao, Chenfei Rao, Zicong Feng, Kun Sun, Xinxin Chen, Yihua He, Hao Zhang, Shoujun Li
Journal: The Lancet Child & Adolescent Health (2023)
Safety of locally administered large surface area microparticle paclitaxel and docetaxel in combination with standard of care cancer therapies.
Authors: Shelagh Verco, Holly Maulhardt, Alyson Marin, Antony Verco
Journal: Journal of Clinical Oncology (2023)

e15187 Background: The safety of local delivery of large surface area microparticle paclitaxel (LSAM-PTX) or docetaxel (LSAM-DTX) to solid tumors has been evaluated in Phase 1/2 trials across 156 subjects with 43% (67/156) on various concurrent standard of care (SOC) therapies. Local administration of LSAM-PTX or LSAM-DTX leads to a reduction in systemic drug exposure and drug-related adverse events (AE) and may reduce toxicities encountered in combination systemic treatment regimens. This report summarizes safety findings in subjects co-administered LSAM-PTX or LSAM-DTX and common SOC therapies for treatment of carcinomas. Methods: During the study follow-up periods, AE and serious AE (SAE) were coded (MedDRA 16.1 -23.1) and assessed (NCI CTCAE 3 - 5). Results: In 7 studies (median age 69 years (range 37-96), 61% male, 88% white) (Table), LSAM-PTX administrations occurred as follows: intraperitoneal (n = 31 subjects), intraprostatic (n = 17), and intratumoral (n = 72). A median of 1 cycle (range 1-6) of LSAM-PTX was administered. LSAM-DTX was injected once into bladder tissue after tumor resection followed by a median of 10 cycles (range 7-10) of intravesical instillation in 36 subjects. 59 subjects (median age 65 (range 48-86), 53% male, 88% white) received local LSAM-PTX and concomitant chemotherapy, immunotherapy, or radiation. Rates of subjects who had Grade 3 SAE possibly related to LSAM-PTX were 29%, 24%, 16%, 6.7% and 5.0% in paclitaxel, carboplatin, 5-FU, nab-paclitaxel, and gemcitabine combinations, respectively. Grade 4 SAE possibly related to LSAM-PTX were found in 1 subject each co-administered pembrolizumab (13%), carboplatin (5.9%), and paclitaxel (7.1%). Subjects treated with 5-FU, gemcitabine, and nab-paclitaxel reported no related Grade 4 SAE. No Grade 5 SAE were deemed possibly related to LSAM-PTX. 8 subjects (median age 78 (range 54-89), 100% male, 88% white) received local LSAM-DTX therapy in combination with SOC therapies. No Grade 3-5 AE were reported with LSAM-DTX in combination with gemcitabine, carboplatin, pembrolizumab, avelumab or radiation. Conclusions: Local treatment of solid tumors with LSAM-PTX or LSAM-DTX has the potential to overcome some limitations of SOC therapies by increasing tumor dwell time and reducing systemic toxicities which are often exacerbated in combinatorial treatment regimens. Clinical trial information: NCT00666991 , NCT03636256 , NCT03077659 , NCT04221828 , NCT03029585 , NCT03077685 , NCT04314895 . [Table: see text]
Salvage endoscopic wide-field full-thickness resection of T2 rectal cancer with endoscopic submucosal dissection instruments, without defect closure
Authors: Georgios Mavrogenis, Dimitrios Ntourakis, Neoklis Kritikos, Panagiotis Kasapidis, Loukas Kaklamanis, Vassilis Kouloulias, Fateh Bazerbachi
Journal: Endoscopy (2023)

A 86-year-old woman was referred for recurrent bleeding secondary to a 4-cm cT2N0 cancer of the distal rectum ([Fig. 1]). Tumor staging was negative for metastasis. She had a history of severe aortic stenosis and atrial fibrillation under anticoagulants, making her a poor candidate for surgical treatment by total mesorectal excision. After a multidisciplinary approach and informed patient consent, we performed a palliative endoscopic resection of the tumor by means of endoscopic submucosal techniques under propofol sedation [(Video 1]).
Metformin with neoadjuvant chemotherapy in localized triple negative and HER2neu-positive breast cancer: A prospective phase 2 open label randomised controlled trial (McBETH).
Authors: Mouna Bidaraguppe B M, akash kumar, Atul Batra, Vinod Sharma, Babita Kataria, Ajay Gogia, Sandeep Mathur, Aparna Sharma
Journal: Journal of Clinical Oncology (2023)

TPS631 Background: Repurposing of drugs in cancer is an attractive strategy and metformin has long been an agent with promising yet unproven activity in breast cancer. Despite some recent studies showing inadequate efficacy in adjuvant setting, there is a lack of well powered studies in neo-adjuvant setting in localised breast cancer. Few past studies suggest that metformin may have anticancer effects in the subsets of Her2 neu positive as well as Triple negative breast cancer (TNBC). We initiated this study to investigate if metformin in combination with standard neo-adjuvant chemotherapy is effective in improving pathological complete response rates in these subsets among localised breast cancers. Methods: This is an investigator initiated randomised, open label, parallel-group superiority trial. All non diabetic localised chemo-naïve breast cancer patients aged ≥18 years planned for neo-adjuvant chemotherapy will be randomly allocated (stratified by HER 2 positive and TNBC) to receive standard neo-adjuvant chemotherapy with or without metformin (850mg twice daily) till the day of surgery. The patients will be followed up until the surgery. The primary objective of this study is to compare the pathological complete response rates(ypT0ypN0) in each arm. The secondary objectives are to compare pathological complete response rates in predefined subsets of HER2 positive and triple negative breast cancer, clinical response rates in each arm, patient reported outcomes in each arm (ESAS-r Scale), breast conservation surgery rates in each arm, incidence and severity of adverse events in both arms. Trial statistical design: Planned accrual is total 242 patients including 10% drop out rate. It is a superiority design with an absolute improvement of 11% in pathological complete response from a baseline of 33% in the standard arm. Conduct to date: study activation: May 2022. Enrolment: 116 subjects. Clinical trial information: REF/2022/05/054208.
Early Circulating Tumor DNA Dynamics and Efficacy of Lorlatinib in Patients With Treatment-Naive, Advanced, ALK-Positive NSCLC
Authors: Ross A. Soo, Jean-François Martini, Anthonie J. van der Wekken, Shunsuke Teraoka, Roberto Ferrara, Alice T. Shaw, Deborah Shepard, Anna Maria Calella, Anna Polli, Francesca Toffalorio, Pascale Tomasini, Chao-Hua Chiu, Dariusz M. Kowalski, Hye Ryun Kim, Benjamin J. Solomon
Journal: Journal of Thoracic Oncology (2023)

Circulating tumor DNA (ctDNA) has been used as a biomarker for prognostication and response to treatment. Here, we evaluate ctDNA as a potential biomarker for response to lorlatinib, a third-generation ALK tyrosine kinase inhibitor in patients with treatment-naive, advanced, ALK-positive NSCLC in the ongoing phase 3 CROWN study (NCT03052608).Molecular responses were calculated using mean variant allele frequency (VAF), longitudinal mean change in VAF (dVAF), and ratio to baseline. Efficacy assessments (progression-free survival [PFS] and objective response rate) were paired with individual patient ctDNA and analyzed for association.Compared with baseline, mean VAF at week 4 was decreased in both treatment arms. Considering all detected somatic variants, a reduction in dVAF (≤0) was associated with a longer PFS in the lorlatinib arm. The hazard ratio (HR) for a dVAF less than or equal to 0 versus more than 0 was 0.50 (95% confidence interval [CI]: 0.23-1.12) in the lorlatinib arm. A similar association was not observed for crizotinib (HR = 1.00, 95% CI: 0.49-2.03). Comparing molecular responders with nonresponders, patients treated with lorlatinib who had a molecular response had longer PFS (HR = 0.37, 95% CI: 0.16-0.85); patients treated with crizotinib who had a molecular response had similar PFS as those without a molecular response (HR = 1.48, 95% CI: 0.67-3.30).In patients with treatment-naive, advanced, ALK-positive NSCLC, early ctDNA dynamics predicted better outcome with lorlatinib but not with crizotinib. These results suggest that ctDNA may be used to monitor and potentially predict efficacy of lorlatinib treatment.
Data to Action: Community-Based Participatory Research to Address Concerns about Metal Air Pollution in Overburdened Neighborhoods near Metal Recycling Facilities in Houston
Authors: Elaine Symanski, Heyreoun An Han, Sheryl McCurdy, Loren Hopkins, Juan Flores, Inkyu Han, Mary Ann Smith, James Caldwell, Cecelia Fontenot, Bobbie Wyatt, Christine Markham
Journal: Environmental Health Perspectives (2023)

Background: Exposures to environmental contaminants can be influenced by social determinants of health. As a result, persons living in socially disadvantaged communities may experience disproportionate health risks from environmental exposures. Mixed methods research can be used to understand community-level and individual-level exposures to chemical and nonchemical stressors contributing to environmental health disparities. Furthermore, community-based participatory research (CBPR) approaches can lead to more effective interventions. Objectives: We applied mixed methods to identify environmental health perceptions and needs among metal recyclers and residents living in disadvantaged neighborhoods near metal recycling facilities in Houston, Texas, in a CBPR study, Metal Air Pollution Partnership Solutions (MAPPS). Informed by what we learned and our previous findings from cancer and noncancer risk assessments of metal air pollution in these neighborhoods, we developed an action plan to lower metal aerosol emissions from metal recycling facilities and enhance community capacity to address environmental health risks. Methods: Key informant interviews, focus groups, and community surveys were used to identify environmental health concerns of residents. A diverse group from academia, an environmental justice advocacy group, the community, the metal recycling industry, and the local health department collaborated and translated these findings, along with results from our prior risk assessments, to inform a multifaceted public health action plan. Results: An evidence-based approach was used to develop and implement neighborhood-specific action plans. Plans included a voluntary framework of technical and administrative controls to reduce metal emissions in the metal recycling facilities, direct lines of communication among residents, metal recyclers, and local health department officials, and environmental health leadership training. Discussion: Using a CBPR approach, health risk assessment findings based on outdoor air monitoring campaigns and community survey results informed a multipronged environmental health action plan to mitigate health risks associated with metal air pollution. https://doi.org/10.1289/EHP11405
A phase 2a study evaluating the efficacy and safety of sutetinib in patients with advanced non–small-cell lung cancer (NSCLC) harboring uncommon EGFR mutations.
Authors: Fengying Wu, Fei Zhou, Fuyou Zhao, Wei Zhang, Lei Wang, Jia Yu, Anweng Xiong, Jing Zhao, Wei Li, Guanghui Gao, Yayi He, Bing Bo, Shuyan Meng, Baohui Han, Caicun Zhou
Journal: Journal of Clinical Oncology (2023)

9131 Background: Although non-small cell lung cancer (NSCLC) patients with tumor harboring classical Epidermal Growth Factor Receptor (EGFR) mutations have numerous therapeutic choices, uncommon EGFR mutation NSCLC patients have limited treatment options. Sutetinib is a selective tyrosine kinase inhibitor (TKI) targeting uncommon EGFR mutations. Methods: In this multicenter, open-label phase 2a study, treatment-naïve adults with NSCLC harboring uncommon EGFR mutations (G719X, S768I, L861Q) received oral sutetinib monotherapy at 80 or 64 mg/day (Chinese trial register CTR20190681). The primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints included duration of response (DoR), overall survival (OS), safety and tolerability. Adverse events (AEs) were graded according to the CTCAE v5.0. Results: Sutetinib was administered to 30 NSCLC patients at 80 (n = 15) or 64 (n = 15) mg/day. Median age was 60 years old (range 47-74 years). Twenty patients (66.7%) were females, 10 patients (33.3%) had a history of smoking. Patients had an ECOG PS of 0 (10.0%) or 1 (90.0%). Tumors had a G719X (36.7%), L861Q (30.0%), or S768I (20.0%) EGFR mutation, or a combination of these uncommon EGFR mutations (13.3%). None had EGFR T790M, L858R, exon 19 deletions, or exon 20 insertions. The ORR was 71.4% (20/28), including 92.9% (13/14) and 50.0% (7/14) in the 80 and 64 mg/day cohorts, respectively. The disease control rate (DCR) was 96.4%, including 100.0% (14/14) and 92.8% (13/14) in the 80 and 64 mg/day cohorts, respectively. All responses were partial responses. The median DoR was 12.5 months (20.3 and 9.2 months in the 80 and 64 mg/day cohorts, respectively). One-year OS was 84.7% (92.9% and 75.0% in the 80 and 64 mg/day cohorts, respectively). As of 15 January 2022 (database lock), 11 (36.7%) patients were still receiving sutetinib treatment. Grade ≥3 treatment emerged AEs were similar in the 80 mg/day (80.0%, 12/15) and 64 mg/day (73.3%, 11/15) cohorts. The most frequently reported grade ≥3 Treatment-related AEs (TRAEs) were diarrhea (36.7%), abnormal liver function (13.3%), and rash (10.0%). One grade 4 TRAE was observed: hypokalemia in the 64 mg/day cohort. Conclusions: Sutetinib demonstrated a high response rate with durable antitumor activity in patients with NSCLC harboring uncommon EGFR mutations. The toxicities are expected and comparable to other EGFR TKIs. A multi-center phase 2b study is ongoing in the United States and China to further evaluate Sutetinib in uncommon EGFR mutation NSCLC. Clinical trial information: CTR20190681 .
Preliminary results of a phase I, first-in-human, dose escalation study of IMM2902 in patients with HER2-expressing advanced solid tumors.
Authors: Yanchun Meng, Jian Zhang, Chuanhua Zhao, Ying Cheng, Liming Zhu, Zhengbo Song, Nong Xu, Zhen Wang, Yanping Wang, Yiqun Du, Deqiang Jing, Dinglu Chen, Qiaofeng Qu, Xiwen Zhao, Wei Li, Qiying Lu, Wenzhi Tian, Jianming Xu
Journal: Journal of Clinical Oncology (2023)

e15185 Background: IMM2902 is a novel recombinant bispecific fusion protein containing SIRPα binding domain trapped to the light chain of a humanized anti-HER2 antibody. With its high affinity to HER2 and CD47 on tumor cell membrane, IMM2902 can drive several anti-tumoral killing mechanisms such as directly targeting HER2 expressing tumor cells; restoring the phagocytic function of macrophages against tumor cells via CD47-SIRPα blockade; activating NK cells and macrophages mediated antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC); and most importantly, inducing accelerated HER2 internalization and degradation. Phase I dose escalation studies of IMM2902 in advanced solid tumors are conducted in both China and the United States, here we present the preliminary results from China trial. Methods: The dose escalation study of IMM2902 was conducted following a modified 3+3 design to evaluate the safety and tolerability of the study drug and to determine the MTD/RP2D. IMM2902 was administered intravenously every week (QW) in 4-week cycles, and the first cycle was the DLT observation period. The tumor responses were evaluated based on RECIST v1.1. IMM2902 pharmacokinetics (PK) and pharmacodynamics (PD) were also evaluated. Results: As of 26 December 2022, a total of 16 subjects had received at least one dose of IMM2902 in 5 dose cohorts (0.03, 0.1, 0.3, 0.9 and 2.0 mg/kg). Of the 16 subjects, no DLTs were observed. Treatment related adverse events (TRAEs) occurred in all 16 subjects (100%), with 4 subjects (25%) reported to have grade 3 TRAEs. No subject discontinued IMM2902 treatment due to TRAEs. The most common TRAEs were platelet count decreased (62.5%), infusion related reaction (50%), and anemia (43.8%). The most common grade 3 or above TRAE was platelet count decreased (18.8%). One SAE (grade 3 gastrointestinal hemorrhage) was reported, which was unrelated to IMM2902. Among 13 evaluable subjects, 4 patients achieved SD (2 pts with gastric cancer at 0.1 mg/kg, 1 pt with skin cancer at 0.9 mg/kg, and 1 pt with breast cancer at 2.0 mg/kg). Preliminary PK analysis showed IMM2902 had a non-linear PK. Serum concentration of IMM2902 reached steady state after the third administration. Preliminary PD data showed that, beginning at 0.3 mg/kg, the number of peripheral CD3 + and CD8 + T-cells increased after 4 weeks of treatment. Conclusions: IMM2902 showed an encouraging preliminary safety, tolerability and anti-tumor activity up to 2.0 mg/kg. The phase I/II study is ongoing. Clinical trial information: ChiCTR20212375 .
Morphologic and molecular analysis of liver injury after SARS-CoV-2 vaccination reveals distinct characteristics
Authors: Sarp Uzun, Carl P. Zinner, Amke C. Beenen, Ilaria Alborelli, Ewelina M. Bartoszek, Jason Yeung, Byron Calgua, Matthias Reinscheid, Peter Bronsert, Anna K. Stalder, Jasmin D. Haslbauer, Juerg Vosbeck, Luca Mazzucchelli, Tobias Hoffmann, Luigi M. Terracciano, Gregor Hutter, Michael Manz, Isabelle Panne, Tobias Boettler, Maike Hofmann, Bertram Bengsch, Markus H. Heim, Christine Bernsmeier, Sizun Jiang, Alexandar Tzankov, Benedetta Terziroli Beretta-Piccoli, Matthias S. Matter
Journal: Journal of Hepatology (2023)

Liver injury after COVID-19 vaccination is very rare and shows clinical and histomorphological similarities with autoimmune hepatitis (AIH). Little is known about the pathophysiology of COVID-19 vaccine-induced liver injury (VILI) and its relationship to AIH. Therefore, we compared VILI with AIH.Formalin-fixed and paraffin-embedded liver biopsy samples from patients with VILI (n = 6) and from patients with an initial diagnosis of AIH (n = 9) were included. Both cohorts were compared by histomorphological evaluation, whole-transcriptome and spatial transcriptome sequencing, multiplex immunofluorescence, and immune repertoire sequencing.Histomorphology was similar in both cohorts but showed more pronounced centrilobular necrosis in VILI. Gene expression profiling showed that mitochondrial metabolism and oxidative stress-related pathways were more and interferon response pathways were less enriched in VILI. Multiplex analysis revealed that inflammation in VILI was dominated by CD8+ effector T cells, similar to drug-induced autoimmune-like hepatitis. In contrast, AIH showed a dominance of CD4+ effector T cells and CD79a+ B and plasma cells. T-cell receptor (TCR) and B-cell receptor sequencing showed that T and B cell clones were more dominant in VILI than in AIH. In addition, many T cell clones detected in the liver were also found in the blood. Interestingly, analysis of TCR beta chain and Ig heavy chain variable-joining gene usage further showed that TRBV6-1, TRBV5-1, TRBV7-6, and IgHV1-24 genes are used differently in VILI than in AIH.Our analyses support that SARS-CoV-2 VILI is related to AIH but also shows distinct differences from AIH in histomorphology, pathway activation, cellular immune infiltrates, and TCR usage. Therefore, VILI may be a separate entity, which is distinct from AIH and more closely related to drug-induced autoimmune-like hepatitis.Little is known about the pathophysiology of COVID-19 vaccine-induced liver injury (VILI). Our analysis shows that COVID-19 VILI shares some similarities with autoimmune hepatitis, but also has distinct differences such as increased activation of metabolic pathways, a more prominent CD8+ T cell infiltrate, and an oligoclonal T and B cell response. Our findings suggest that VILI is a distinct disease entity. Therefore, there is a good chance that many patients with COVID-19 VILI will recover completely and will not develop long-term autoimmune hepatitis.